Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000484392 | SCV000570993 | likely pathogenic | not provided | 2017-06-30 | criteria provided, single submitter | clinical testing | The R975W variant in the CARD11 gene has been reported previously in an individual with severe atopic dermatitis; the R975W variant was also present in the individual's mother who had a history of eczema when younger that improved over time (Ma et al., 2017). The R975W variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R975W variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. Functional studies of the R975W variant demonstrated a damaging effect with disruption of NF-KB activation by wild type CARD11 when co-transfected with R975W (Ma et al., 2017). We interpret R975W as a likely pathogenic variant. |
| Labcorp Genetics |
RCV003766695 | SCV004573277 | uncertain significance | Severe combined immunodeficiency due to CARD11 deficiency; BENTA disease | 2023-03-08 | criteria provided, single submitter | clinical testing | The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 975 of the CARD11 protein (p.Arg975Trp). This missense change has been observed in individual(s) with atopic dermatitis (PMID: 28628108). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects CARD11 function (PMID: 28628108). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CARD11 protein function. ClinVar contains an entry for this variant (Variation ID: 421704). |
| OMIM | RCV000499590 | SCV000590950 | pathogenic | Immunodeficiency 11b with atopic dermatitis | 2017-08-22 | no assertion criteria provided | literature only |